Osteoarthritis (OA) is the leading cause of physical disability in older age, afflicting nearly 27 million Americans, at an estimated annual cost burden of over $80 billion. Although treatments that alleviate OA symptoms exist, there is currently no proven therapy to reduce OA progression. Observational studies suggest vitamin K insufficiency is associated with greater risk for OA. Several vitamin K-dependent (VKD) proteins are present in joint tissues, suggesting vitamin K may be implicated in more than one pathological pathway in OA. In order to function, VKD proteins must undergo a post-translational carboxylation, which requires vitamin K. Matrix gla protein (MGP) is a VKD protein identified in human articular cartilage and considered an important player in reducing soft-tissue calcification, which is a characteristic of OA that affects OA progression. Without sufficient vitamin K, MGP is not able to inhibit calcification. Vitamin K has also been shown to regulate expression of genes implicated in OA pathology. These observations together suggest vitamin K may be involved in multiple aspects of OA pathophysiology. However, it is currently unclear how vitamin K influences OA pathology because mechanistic studies have not been undertaken. The overall career objective of the principle investigator (PI) is to become an independent translational scientist (incorporating basic and clinical science), focusing on the nutritional modulation of OA and related disability. Her research experience to date has focused primarily on observational and clinical studies, which are not able to test hypotheses to clarify mechanistic pathways. The proposed research and training are designed to provide the PI with an in-depth knowledge of OA pathology and a comprehensive laboratory skill-set to be able to study mechanisms underlying the role of nutrients in OA progression and disease management. This training will take place under the mentorship of Dr. Richard Loeser, a translational expert in OA, at Wake Forest University. The training and research together will complement her experience to date, so that she can develop an independent translational research program that utilizes clinical and laboratory-based studies focused on the nutritional modulation of joint health, which is her long-term goal. Identifying nutritional pathways that are implicated in the maintenance of healthy joint tissues may provide important and novel therapeutic targets for improving physical function and quality of life for persons with OA. PUBLIC HEALTH RELEVANCE: Osteoarthritis is the leading cause of lower-extremity disability, afflicting nearly 27 million Americans, and there is currently no proven therapy to delay its progression. Low vitamin K status has been associated with more severe osteoarthritis population-based studies. While vitamin K dependent processes are implicated in joint function, mechanisms of how vitamin K affects OA have not been well-studied. A better understanding of how vitamins K influences osteoarthritis progression is important because nutrient intakes are modifiable and may represent a novel and achievable approach by which to reduce disease progression.